NEW
BRUNSWICK/PISCATAWAY, N.J. – A new tactic in the
battle against cardiovascular disease – employing
nanoengineered molecules called "nanolipoblockers" as
frontline infantry against harmful cholesterol – is
showing promise in early laboratory studies at Rutgers,
The State University of New Jersey.
In a paper scheduled for publication June 12 in
the American Chemical Society's journal Biomacromolecules
and now appearing on that journal's Web site, Rutgers
researchers propose a way to combat clogged arteries
by attacking how bad cholesterol triggers inflammation
and causes plaque buildup at specific blood vessel
sites. Their approach contrasts with today's statin
drug therapy, which aims to reduce the amount of
low density lipids, or LDLs ("bad" cholesterol),
throughout the body.
In an ironic twist, the Rutgers approach aims to
thwart a biological process that is typically beneficial
and necessary. Prabhas Mogue, the principal investigator
and associate professor of biomedical engineering
and chemical and biochemical engineering at Rutgers,
said that vascular plaque and inflammation develop
when certain forms of LDL are attacked by white blood
cells that scavenge cellular debris and disease agents. "While
these scavengers, called macrophages, perform an
essential role in keeping organisms healthy, their
interaction with highly oxidized LDL molecules has
quite the opposite effect," he said.
Mogue explains that macrophages accumulate large
amounts of oxidized LDL and secrete chemicals that
can damage the neighboring tissues and, ultimately,
become fatty foam cells. The researchers' approach,
therefore, is to create clusters of nanoengineered
molecules that target specific receptor molecules
on cell membranes and block these oxidized LDLs from
attaching to macrophages.
Mogue is working with Kathryn Uhrich, Rutgers professor
of chemistry and chemical biology, who is an expert
at synthesizing biologically useful molecules at
the nanoscale – anywhere from 10 to 100 nanometers
long. The research team, which also includes graduate
student Evangelia Chnari and synthetic chemists Lu
Tian and Jinzhong Wang, has designed a family of
nanolipoblockers, or NLBs, which compete with oxidized
LDL for a macrophage's attention. The NLBs bind to
receptor sites on macrophages, cutting the accumulation
of oxidized LDL by as much as 75 percent.
The NLB particles are made of several engineered
organic strands or chains whose ends cluster around
a central point, creating a structure known as a
micelle. Uhrich synthesized molecule chains with
several different characteristics, such as attracting
or repelling water or having a positive or negative
charge. When the chains assembled into micelles,
Mogue tested them for how well they blocked LDL uptake.
"We're employing the tools of nanotechnology – specifically
tailoring the structure of the molecule, changing
groups on the ends of the chains and closely analyzing
which forms of the particles bind to the different
macrophage receptors," Uhrich said. "The significant
finding of our study is that the nanoscale organization
matters tremendously for blockage of oxidized LDL,
which opens new avenues for more specific targeting
of receptors."
Mogue said that if this method proves feasible in
living organisms, it could convey treatment to the
site of the problem, rather than a systemic approach. "While
statins are a great stride in preventing cardiovascular
disease, they are not suitable for everyone," Mogue
said. "Our approach also has potential to topically
address the recurrence of inflammation and blockage
at stent surgery sites, something that systemically
active drugs have not been shown to consistently
do."
Research to test the performance of NLBs in living
organisms is now under way.
The study was supported by grants from the National
Science Foundation and the American Heart Association. |
